Inducing and targeting of EBV lytic antigens in lymphoma. Epstein-Barr Virus (EBV) positive lymphomas include lymphomas in the post-transplantation setting, Burkitt's lymphomas (BL), AIDS- related lymphomas (ARL), and some forms of Hodgkin, T-cell, and natural killer (NK) cell lymphomas. These tymphomas are aggressive malignant lymphomas and often become chemotherapy resistant. A clear need exists to develop novel therapeutic approaches. This research plan proposes to exploit the EBV virus as a specific lymphoma target. EBV is a herpesvirus with two different life cycles: the productive =tytic" cycle leading to the production and release of new virions and the non-productive "latent" cycle. Most lymphoma cells are infected with latent EBV, and only ten viral are expressed at low levels. NF-kappaB plays a critical role in regulating the switch between latency and lytic replication of EBV. Proteasome inhibitors, by inhibiting NF-kB were found to reactivate latent EBV from latently-infected cells in vitro. The underlying HYPOTHESIS is that the proteasome inhibitor Bortezomib (Velcade TM) can be used to initiate EBV lytic antigen expression in EBV-related malignancies, initiating the expression of viral TK and other viral antigens, thereby rendering the tumor cells susceptible to killing by the nucleoside analogue Gancyclovir and cells of the immune system. This novel combination therapy will be developed specifically for the treatment of patients with EBV+ lymphomas. AIM 1: Define the conditions by which proteasome inhibitor Bortezomib can reactivate latent EBV from EBV+ lymphoma cells and sensitize these cells to Gancyclovir in cell culture and a mouse EBV+ lymphoma -xenograft model. Determine the contribution of reactivation, by-standing killing and immune responses to the new therapeutic approach. AIM 2: Initiate a feasibility study beginning year 2 of the funding period, testing the safety and efficacy of the combination of proteasome inhibitor Bortezomib with Gancyclovir in patients with EBV* lymphomas. Determine the molecular events associated with the treatment. In summary, the proposed clinical protocol represents a novel application of proteasome inhibitors derived from the understanding of EBV biology, and aims to develop a novel, less toxic, biologic treatment protocol for EBV + lymphomas. As clearly demonstrated by his CV, the applicant has committed himself to a career in translational research in the field of lymphoma. This 3-year Career Development Plan aims to facilitate the required additional training and the translation of a basic science discovery to the clinic in form of a feasibility trial. We anticipate a successful clinical trial and plan the extension to a larger multi center clinical trial in the time following the K23 granting period.